Neoadjuvant chemotherapy (NACT) is often used in the management of patients with locally advanced breast cancer. It can improve outcomes by early treatment of micro-metastases, downstaging the disease, and increasing breast conserving surgery rates. However, NACT is met with heterogeneous outcomes. While 70- 80% of the patients demonstrate some degree of response, only approximately 25% achieve a pathologic complete response, the only outcome shown to correlate with improved survival. Such variability has motivated the development of therapy monitoring techniques to identify ineffective treatments, especially given recent data showing response guided NACT may lead to increased survival. Monitoring may be particularly important for triple negative breast cancer, and with the increasing use of targeted agents. The best sensitivity to early response is provided by functional imaging methods, because changes in tumor physiology occur before actual tumor shrinkage. Near infrared diffuse optical spectroscopy and imaging (NIR-DOSI) is emerging as a promising non-invasive tool for probing the tumor microenvironment. Our group has been one of the pioneers of dynamic optical imaging, which is able to probe the response of breast tissue to external stimuli, in addition to quantifying baseline hemoglobin concentration and oxygenation. In particular, we have recently shown that, prior to treatment, breast cancer tumors exhibit delayed reperfusion and a persistent reduction in hemoglobin oxygen saturation (SO2) vs. the surrounding healthy tissue during the viscoelastic relaxation phase following fractional mammographic like compression. This response is likely determined by the interplay of the increased stiffness and interstitial fluid pressure, and the higher metabolic rate of malignant lesions. Preliminary data indicates these differences nearly disappear by 30 days into NACT for responding tumors, while persisting for non-responding ones, suggesting dynamic optical imaging could be used to probe the tumor biomechanical properties. Tumor stiffness and increased IFP have been shown to cause poor drug delivery and correlate with an increased likelihood of metastasis. Improved blood flow through vascular normalization, and reduction of internal stresses using anti-fibrotic agents are promising new avenues of cancer therapy development. Dynamic optical imaging can help this endeavor as a versatile non-invasive tool that probes both the vascular (through total hemoglobin concentration (HbT) and SO2) and biomechanical tumor properties (through monitoring the hemodynamic response to compression). The goal of this project is to validate the variation of tissue HbT and SO2 due to breast compression as biomarkers for guiding breast cancer neoadjuvant chemotherapy. Our main approach is to develop a combined optical+x-ray mammography scanner for ease of clinical translation, but we will also employ Magnetic Resonance Imaging and MR Elastography to investigate the physiological basis of the compression response.